Pasireotide is a synthetic long-acting cyclic hexapeptide with somatostatin-like activity. It is chemically known as (2-Aminoethyl) carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-(4-aminobutyl)-5-benzyl-8-(4-benzyloxybenzyl)-14-(1H-indol-3ylmethyl)-4,7,10,13,16,19-hexaoxo-17-phenyloctadecahydro-3a,6,9,12,15,18-hexaazacyclopentacyclooctadecen-2-yl-ester. It is marketed as a diaspartate salt called Signifor®, which is used in the treatment of Cushing's disease.
The cyclic peptide sequence of Pasireotide is represented as Cyclo[Phe-{4-(OCO—NH—CH2—CH2—NH2)) Pro}-Phg-DTrp-Lys-Tyr(Bzl)].
U.S. Pat. No. 7,473,761 discloses Pasireotide along with other somatostatin analogues. Not many synthetic procedures for Pasireotide are known in the art. US publication 20110166320 discloses a method for the preparation of Pasireotide by solid phase synthesis. The process involves, sequential addition of amino acids (Fmoc/Boc strategy) using an automated peptide synthesizer, in the presence of suitable resin. To attain the target peptide Pasireotide, any of the following sequences could be employed.
DTrp-Lys-Tyr(Bzl)-Phe-{4-(OCO-NH-CH2-CH2-NH2)Pro}-Phg, Phg-DTrp-Lys-Tyr(Bzl)-Phe-{4-(OCO-NH-CH2-CH2-NH2)Pro}, {4-(OCO-NH-CH2-CH2-NH2)Pro}-Phg-DTrp-Lys-Tyr(Bzl)-Phe, Phe-{4-(OCO-NH-CH2-CH2-NH2)Pro}-Phg-DTrp-Lys-Tyr(Bzl), Tyr(Bzl)-Phe-{4-(OCO-NH-CH2-CH2-NH2)Pro}-Phg-DTrp-Lys,and Lys-Tyr(Bzl)-Phe-{4-(OCO-NH-CH2-CH2-NH2)Pro}-Phg-DTrp
Thus the above 6 amino acid sequence yields respective linear peptide chains. The peptide chain is either cleaved from resin using suitable reagent, deprotected and then cyclized or first cyclized followed by removal of protecting groups.
Therefore, the process of US publication number 20110663260, essentially involves usage of amino acid proline substituted with an ethylene diamine at the ‘4’ position. This would sterically hinder the peptide formation and thereby suffers in low peptide yield.